The asymmetric divisions of neural progenitors are an important regulator of neural fate. Studies over the past 20 years have identified mechanisms that distribute developmental potential and orient the spindle in these divisions. Much less, however, is known about a subset of these divisions that produce daughter cells of different sizes, what I refer to here as Daughter Cell Size Asymmetry (DCSA). DCSA has been observed in cell divisions that range from the C. elegans zygote to mouse cortical progenitors. We propose to study DCSA in the Q.a and Q.p neural progenitors, where it contributes to the apoptotic fate. These cells provide an excellent model for the study of DCSA because they use two different mechanisms for DCSA: Q.a divides asymmetrically by a myosin-dependent, spindle-independent mechanism, and Q.p by a spindle-dependent mechanism. These studies have important implications for human health: dysregulation of cortical progenitor divisions can result in lissencephaly and microcephaly, and Wnt signaling, which is dysregulated in several cancers, regulates Q division asymmetry. The overall goal of our studies is to understand how these types of asymmetric divisions regulated. Our work has identified both Wnt signaling and the conserved molecules PIG-1, HAM-1 and TOE-2 as playing crucial roles in DCSA. Our working model proposes that the localization of PIG-1 controls membrane extension through GTPases of the Rho family and spindle movement through trimeric G proteins. It also proposes that Wnt signaling regulates both the myosin-dependent, spindle-independent and the spindle-dependent mechanisms through the PIG-1 and that HAM-1, TOE-2 and MAP kinase signaling switch Wnt signaling from a default spindle-dependent mechanism to a spindle-independent mechanism. A combination of genetic, molecular and imaging approaches will be used to test these hypotheses.